Long Noncoding RNA uc002yug.2 Activates HIV-1 Latency through Regulation of mRNA Levels of Various RUNX1 Isoforms and Increased Tat Expression
Long Noncoding RNA uc002yug.2 Activates HIV-1 Latency through Regulation of mRNA Levels of Various RUNX1 Isoforms and Increased Tat Expression
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DOI：
10.1128/jvi.01844-17
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发表时间：
2018-05-01
影响因子：
5.4
通讯作者：
Zhang, Wenyan
中科院分区：
文献类型：
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作者：
Huan, Chen;Li, Zhaolong;Zhang, Wenyan
HIV-1的宿主是彻底根除该病毒的主要障碍。虽然许多蛋白质和RNA已被鉴定为HIV-1/AIDS发病机制和潜伏期的调节因子，但只有少数长的非编码RNA（lncRNA）已被证明与HIV-1复制和潜伏期密切相关。在这项研究中，我们证明了lncRNA uc002yug.2在HIV-1复制和潜伏期中起着关键作用。uc002yug. 2可能增强HIV-1复制，长末端重复序列（LTR）活性，并激活潜伏的HIV-1在细胞系和患者的CD 4（+）T细胞。进一步的研究显示uc 002 yug.2通过下调RUNX 1b和-1c以及上调达特蛋白表达来激活潜伏的HIV-1。累积的证据支持我们的模型，即达特蛋白在uc 002 yug.2介导的调节HIV-1再活化的作用中具有关键作用。而且，uc 002 yug. 2显示出类似于辛二酰苯胺异羟肟酸或佛波醇12-肉豆蔻酸酯13-乙酸酯的激活HIV-1的能力。这些发现提高了我们对lncRNA调节HIV-1复制和潜伏期的理解，为潜在的靶向治疗干预提供了新的见解。潜伏的病毒库是治疗HIV-1疾病的主要障碍。迄今为止，只有少数lncRNA，在各种生物过程中发挥重要作用，包括病毒感染，已被确定为HIV-1潜伏期的调节剂。在这项研究中，我们证明了lncRNA uc002yug.2对HIV-1复制和潜伏病毒的激活都很重要。此外，uc 002 yug.2显示通过调节RUNX 1的选择性剪接和增加达特蛋白的表达来激活潜伏的HIV-1。这些发现突出了靶向lncRNA uc 002 yug的潜在优点。2作为潜伏HIV-1的活化剂。
The HIV-1 reservoir is a major obstacle to complete eradication of the virus. Although many proteins and RNAs have been characterized as regulators in HIV-1/AIDS pathogenesis and latency, only a few long noncoding RNAs (lncRNAs) have been shown to be closely associated with HIV-1 replication and latency. In this study, we demonstrated that lncRNA uc002yug.2 plays a key role in HIV-1 replication and latency. uc002yug. 2 potentially enhances HIV-1 replication, long terminal repeat (LTR) activity, and the activation of latent HIV-1 in both cell lines and CD4(+) T cells from patients. Further investigation revealed that uc002yug.2 activates latent HIV-1 through downregulating RUNX1b and -1c and upregulating Tat protein expression. The accumulated evidence supports our model that the Tat protein has the key role in the uc002yug.2-mediated regulatory effect on HIV-1 reactivation. Moreover, uc002yug. 2 showed an ability to activate HIV-1 similar to that of suberoylanilide hydroxamic acid or phorbol 12-myristate 13-acetate using latently infected cell models. These findings improve our understanding of lncRNA regulation of HIV-1 replication and latency, providing new insights into potential targeted therapeutic interventions. IMPORTANCE The latent viral reservoir is the primary obstacle to curing HIV-1 disease. To date, only a few lncRNAs, which play major roles in various biological processes, including viral infection, have been identified as regulators in HIV-1 latency. In this study, we demonstrated that lncRNA uc002yug.2 is important for both HIV-1 replication and activation of latent viruses. Moreover, uc002yug.2 was shown to activate latent HIV-1 through regulating alternative splicing of RUNX1 and increasing the expression of Tat protein. These findings highlight the potential merit of targeting lncRNA uc002yug. 2 as an activating agent for latent HIV-1.